Peripheral neuropathy is the dysfunction of one or more peripheral nerves (the part of a spinal nerve distal to the root and plexus). It includes numerous syndromes characterized by varying degrees of sensory disturbances, pain, muscle weakness and atrophy, diminished deep tendon reflexes, and vasomotor symptoms, alone or in any combination. Electromyography and nerve conduction velocity studies help localize the lesion and determine whether the pathophysiology is primarily axonal (often metabolic) or demyelinating (often autoimmune).
Peripheral neuropathy associated with diabetes (diabetic neuropathy) is a polyneuritis linked to the duration poor control of the underlying diabetes. It can affect the upper and lower limbs and the cranial nerves.
Diabetic neuropathy is the consequence of an impairment of certain nerves caused by diabetes. These nerves can be located anywhere in the organism, with some areas being more “at risk” than others. Depending on the type of nerves affected and the place where they are located in the organism, generally three kinds of diabetic neuropathy are distinguished.
The most frequent form is distal symmetrical polyneuropathy. This disease involves an impairment of several nerves (poly means several in Greek) in the two lower limbs (symmetrical) and is generally especially manifest in the feet (distal).
Diabetic pain is generalized and does not affect only one single organ unlike certain other types of pain, which are localized.
Known treatments of pain associated with peripheral, in particular diabetic neuropathies, include topical agents, tricyclic antidepressants, anticonvulsants, and nonoploid analgesics.
Botulinum toxin, in particular botulinum toxin type A1 (Dysport® marketed by ipsen or Botox® marketed by Allergen), has been used for human therapy since the 1980s. The diseases/disorders treated with botulinum toxin include e.g. muscle disorders (for example blepharospasm, spasticity in adults or children or torticollis), migraine, pain of muscular origin, hyperhidrosis (excessive perspiration), hypersalivation. In cosmetic applications, botulinum toxin is used to treat wrinkles.
WO 01/26736 discloses a method of treating pain associated with diabetes by intrathecal (intraspinal) administration of botulinum neurotoxin type A. This document teaches that the injected neurotoxin does not diffuse or is transported away from the CNS injection site.
US 2002/0192239 describes treatment of neuralgia-related chronic severe pain or post-operative incisional wound pain by injecting botulinum toxin into an afflicted area of a patient.
US 2004/0247623 describes the transdermal administration of botulinum toxin type A for treatment of migraine or other disorders associated with the release of certain neurotransmitters from sensory neurons. One such disease can be diabetic neuropathy. US 2004/0247623 teaches to apply the botulinum toxin directly into the affected area.
Bach-Rojecky et al. (Journal of Neural Transmission 2005, vol. 112, no. 2, p. 215-219) disclose the reduction of thermal and mechanical hyperalgesia by botulinum toxin type A in an experimental model of neuropathic pain caused by surgical neuropathy.
Argoff (Clinical Journal of Pain 2002, New York, vol. 18, no. 6, p. s177-s181) describes a study using botulinum toxin type A injections into the site of maximal pain in patients suffering from CRPS type I (Complex Regional Pain Syndrome). The patients experienced relief of their burning and dysesthetic pain in the affected extremities.
Attal et al. (Neurology 2008, vol. 70, no. 11, Suppl. 1, page A167) disclose an analgesic effect of botulinum toxin type A in patients with focal painful neuropathies upon injection into the painful area.
Lo Nigro et al. (Medical and Pediatric Oncology 2002, vol. 38, no. 2, page 150) describe a 2-year old child suffering from leukaemia and chemotherapy induced peripheral neuropathy. The child also suffered from congenital spastic contractures of the right leg, which were treated by local administration of botulinum toxin into the spastic muscle every 3 months until relaxation became manifest.
Ansiaux et al. (Expert Opinion on Investigational Drugs 2007, vol. 16, no. 2, pages 209-218) report the use of botulinum toxins in cancer therapy, in particular an effect of botulinum toxins to inhibit neurogenic contractions of tumor vessels in order to potentiate cytotoxic therapy.
An analgesic effect of botulinum toxin at a site which is distant from a local injection site for treatment of pain associated with diabetic neuropathy has not been described in the prior art.